The major goals of this competing renewal of this Program Project Grant (PPG) are to advance understanding of the etiology and pathogenesis of frontotemporal lobar degeneration (FTLD) spectrum disorders with a specific emphasis on patients with aggregated tau pathology (FTLD-Tau), so as to improve the diagnosis and treatment of patients with FTLD-Tau disorders and related diseases. FTLD, referred to clinically as frontotemporal degeneration (FTD), manifests with progressive behavioral and/or language deficits but neuropathologically, FTLD is heterogeneous, with ~50% of cases characterized by TDP-43 (i.e. FTLD-TDP subtype) or tau (FTLD-Tau) pathology, while rare cases are due to FUS pathology (i.e. FTLD-FUS). Since clinical diagnoses do not precisely predict the underlying neuropathology of different FLTD variants, and since potential treatments for these different subtypes of FTLD (e.g. targeting the removal of tau versus TDP-43 pathology) are likely different, it is imperative that we develop a better understanding of the clinical, genetic, biochemical, biomarker and neuropathological phenotypes as well as the molecular abnormalities in patients with the spectrum of FTLD diseases. The focus of this PPG is on FTLD-Tau diseases that progressively accumulate distinct pathological tau species that we refer to here as strains in different tauopathy variants including corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and Pick's disease (PiD) in a distinct and stereotypical manner. The pathological tau strains propagate through the neuroanatomical connectome and glial cells producing patterns of tau pathology mediated neurodegeneration that reflect the clinical and pathological diversity of these tauopathies. Thus, the overarching objectives of the overall PPG which is comprised of 5 Cores and 4 Projects, are to test the transmission hypothesis and the strain hypothesis of pathological tau spread in patients and in model systems by: 1) characterizing the spectrum of the clinical phenotypes seen in FTD patients; 2) identifying new genetic mutations in FTLD-Tau kindreds as well as novel genetic modifiers of tau pathogenicity through human postmortem brain expression analyses; 3) developing novel neuronal culture and animal models of FTLD-Tau disorders using FTLD brain-derived tau strains; 4) elucidating the molecular basis of cell-to-cell spread involving uptake, release and intracellular trafficking of pathological tau; 5) transmission of tau pathology in brains of transgenic mouse models injected with tau strains purified from human PSP, CBD and PiD brains. By addressing these and other closely related questions defined in each of the Projects with the innovative approaches described here, this PPG will advance understanding of the onset and progression of FTLD-Tau disorders, especially PSP, CBD and PiD, as well as open up new directions for the accurate and early diagnosis of these tauopathies and novel ways to develop disease modifying therapies to prevent or treat them.